A peptide that inhibits function of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) reduces lung cancer metastasis

Abstract

Myristoylated Alanine-Rich C Kinase Substrate (MARCKS), a substrate of protein kinase C, is a key regulatory molecule controlling mucus granule secretion by airway epithelial cells as well as directed migration of leukocytes, stem cells and fibroblasts. Phosphorylation of MARKCS may be involved in these responses. However, the functionality of MARCKS and its related phosphorylation in lung cancer malignancy have not been characterized. This study demonstrated elevated levels of MARCKS and phospho-MARCKS in highly invasive lung cancer cell lines and lung cancer specimens from non-small-cell lung cancer patients. siRNA knockdown of MARCKS expression in these highly invasive lung cancer cell lines reduced cell migration and suppressed PI3K (phosphatidylinositol 3′-kinase)/Akt phosphorylation and Slug level. Interestingly, treatment with a peptide identical to the MARCKS N-terminus sequence (the MANS peptide) impaired cell migration in vitro and also the metastatic potential of invasive lung cancer cells in vivo. Mechanistically, MANS peptide treatment resulted in a coordination of increase of E-cadherin expression, suppression of MARCKS phosphorylation and AKT/Slug signalling pathway but not the expression of total MARCKS. These results indicate a crucial role for MARCKS, specifically its phosphorylated form, in potentiating lung cancer cell migration/metastasis and suggest a potential use of MARCKS-related peptides in the treatment of lung cancer metastasis.

A Novel Predictor of Cancer Malignancy: Up-regulation of Myristoylated Alanine-Rich C Kinase Substrate Phosphorylation in Lung Cancer

“…This is because MARCKS expression is ubiquitous in various normal and tumor tissues. Despite this, there is a consensus that phospho-MARCKS, a post-translational modification, is associated with cell motility, and has a role in the regulation of cancer cell invasiveness and metastasis (2,4,14,15). Of note, our laboratory discovered that inhibition of MARCKS phosphorylation was able to reduce lung cancer metastasis in murine models (2).…”

“…Thus, development of biomarkers to identify patients at high risk for aggressive progression is of urgent need. Recently, we have reported myristoylated alanine-rich C kinase substrate (MARCKS), predominantly its phosphorylated state, as a risk factor associated with lung cancer invasiveness and metastasis (2). MARCKS is a substrate of protein kinase C, and also a membrane-associated protein.…”

Targeting Myristoylated Alanine-Rich C Kinase Substrate Phosphorylation Site Domain in Lung Cancer. Mechanisms and Therapeutic Implications

“…Phosphorylation by protein kinase C (PKC) within MARCKS PSD (Ser159, Ser163, and Ser170) enhances phosphorylated MARCKS (phospho-MARCKS) detachment from membrane and suppresses PIP2 sequestering effect (15,16). In the lung, MARCKS, predominantly phospho-MARCKS, is crucial for controlling mucin secretion and inflammation (17)(18)(19)(20)(21), but only a few studies have revealed its relevance with lung cancer (22,23). Recently, our laboratory discovered that the use of a MANS peptide, targeting MARCKS N-terminal myristoylation site, was able to reduce lung cancer metastasis.…”

MARCKS Is Marked in Combating Lung Cancer Growth and Acquired Resistance

“…In another recent study, the authors have shown that a peptide corresponding to the N terminus (myristoylated N-terminal sequence [MANS]) of MARCKS, termed MANS peptide (14), reduced lung cancer metastasis but had no effect on tumor growth in a preclinical model (13). In contrast, MSP peptide diminished both PIP3 pools and phospho-MARCKS levels by specifically suppressing MARCKS PSD activity (6).…”

“…Importantly, in the present study, Chen and colleagues found increased levels of phospho-MARCKS as a predictor of poor survival rates among patients with lung cancer specifically receiving EGFR-TKIs. In a preclinical model, they show that 25-mer peptide targeting PSD of MARCKS (or MSP) (12) markedly reduces lung tumor growth and metastasis in mice (13). Importantly, this peptide acts synergistically with erlotinib and exhibits efficacy in the inhibition of tumor growth, metastasis, and erlotinib resistance (6).…”